Pyridazone derivatives



April 29, 1969 H. M. LABORIT I3,441,565

PYRIDAZONE DERIVATIVES Filed Feb. 21, 1966 R R2 R1 Eigl /CH2 C\0 (Il) @l zo (m) COOH United States Patent O U.S. Cl. 260-247.2 Claims ABSTRACT OF THE DISCLOSURE The new derivatives are 4-alkyl-5-H or alkyl-6-phenyl or substituted phenyl-3-pyridazones or corresponding 4- hydroXy-pyridazinones substituted at position 2 by a dialkylaminoalkyl -group or a nitrogenated heterocycle-N- alkyl group. They are useful as psychotropic compounds.

The present invention relates to a family of new chemical compounds having therapeutic properties.

These compounds are those of general formula wherein R is at least a substituent in ortho, metaor para-position consisting of hydrogen, halogen, an alkyl, alkoxy or hydroxy group, R1 is an alkyl group having 1-4 carbon atoms, R2 is hydrogen or an alkyl group havin-g 1-4 carbon atoms, X is hydrogen or a lower alkyl group n is an integer equal to 1 or more, the various Xs, when n is greater than l, not being necessarily identical, Z1 and Z2 are alkyl groups or, together with the nitrogen atom to which they are attached, form a heterocyclic nucleus which can comprise heteroatoms other than the nitrogen atom, and R3 is hydrogen and R., is an OH group or R3 and R4 form together a double bond, together with their acid addition salts, and particularly of pharmaceutically acceptable salts.

Thus compounds (A) are the substituted 6-pheny1-3- pyridazones (I) of formula illustrated in FIG. 1 of the accompanying drawing, and the substituted 6-phenyl-3- pyridazinones (VI bis) having the formula given in FIG. 2 and from which compounds (I) are derived by dehydration.

The compounds (A) have a psychotropic action, namely they participate in treatments affecting the central nervous system.

The psychotropic action of these compounds appears to `depend on the simultaneous presence on the pyridazone nucleus of an alkyl group (R1) at position 4 and of a nitrogen atom on the side-chain attached to the nitrogen at position 2, separated from the latter by at least one carbon atom (group (CHX)D).

To prepare these compounds, an original process is employed, the main stages of which are illustrated in FIG. 2 of the accompanying drawing.

This process is characterised -by the use, as starting materials, of a-alcohol-fy-ketonic acids (1V) which are themselves prepared (stage a) by cold condensation in the presence of potassium hydroxide or other alkaline base in methanol or some other suitable solvent, of aryl-ketones (Il), with the alkali metal salts of -ketonic acids (III). After neutralization and removal of the solvent in vacuo, the remaining solution is extracted in an acid medium with ether -or some other suitable solvent. The desired acid (IV) is extracted by dissolution in a bicarbonate solution followed by precipitation in an acid medium.

3,441,565 Patented Apr. 29, 1969 Starting from the a-alcohol-'y-ketonic acid (IV) thus obtained, the process according to the invention comprises condensing this acid or an ester thereof with a hydrazine of general formula H2N-NH-R5 wherein R5 is hydrogen or a group:

-(CHX)-N thereby obtaining a pyridazinone of formula if desired, dehydrating this pyridazinone into the corresponding pyridazone and, where yR5 is hydrogen, introducing the -(CHX)n-N group by condensation with a halide of formula Y-(CHX)-N wherein Y is halogen, the dehydration and this condensation taking place in any order with respect to one another.

By this latter term is meant that condensation can be eiected either prior to or after dehydration.

The various stages of the process will now be examined in greater detail with reference to FIG. 2. For purposes of clarity the case where, in hydrazine H2N-NHR5, R5 is hydrogen and is distinguished from that where R, is

Thus, condensation of the a-alcohol-'y-ketonic acid (IV) with unsubstituted hydrazine (V) constitutes stage b, whereas condensation with substituted hydrazine (V bis) constitutes stage b1.

The condensation with hydrazine according to stage b or b1 is carried out in an appropriate solvent, such as butanol, which permits, owing to the formation of an azeotrope, the removal of the two water molecules resulting from the condensation. It should be noted this condensation can the carried out just as well with a-alcohol-y-ketonic acids (IV) in the form of simple esters (such as methyl, ethyl or other simple esters).

Pyridazinones (VI and VI bis) constitute new cornpounds.. While the former (VI) do not exhibit to any appreciable degree therapeutic properties and thus simply constitute intermediates this is not so with the latter (VI bis). Indeed, compounds (VI bis) exhibit therapeutic properties closely related to those of the corresponding deyhdrated compounds: pyridazones (I). Thus, the process may be interrupted on production of compounds (VI bis).

On the other hand, when it is desired that the process results in the production of compounds (I) that are sometimes more active than compounds (VI bis), it is necessary that a dehydration be effected.

This dehydration may be effected both with compounds (VD-stage c-and with compounds (VI ibis)-stage c1.

It is carried out by moderate heating of the pyridazinone insolution in an acid medium so as to produce the corresponding pyridazone which is separated by precipitation in cold water. As this dehydration concerns a tertiary hydroxyl group, it is carried out with a very good yield. This is one of the original features and one of the great advantages of the process according to the invention with respect to the known technique, resulting from the choice, in accordance with the invention, of u-alcohol- 'y-ketonic acids (IV) as starting product. It should be noted that this dehydration is not necessarily preceded by the isolation of the pyridazinone. In fact, stages b and c or b1 and c1 may be carried out as a single stage by heating acid (IV) with hydrazine (V or V bis) in acetic medium and in the presence of a small amount of hydrochloric acid.

Stage c1 results directly in the production of therapeutically active pyridazone (I). On the other hand, at the end of stage c, there is obtained a pyridazone (VII) unsubstituted at 2 that should be further aminoalkylated at said position. For this purpose (stage d) pyridazone (VII) is condensed -with an aminoalkyl halide (compound VIII, Y=halogen). The condensation may be effected in the presence of an alkali metal alkoxide such as sodium methoxide or ethoxide in the corresponding alcohol. As a modification, this condensation may be carried out in water, in the presence of an alkaline base such as sodium hydroxide.

For the sake of convenience in the disclosure, stages c and d are described above in that order of succession. This, indeed, is one of the possible procedures. However, stages c and d may occur in the reverse order (not illustrated, for purposes of clarity of the drawing). In the latter case, pyridazinone (VI) is submitted to aminoalkylation to produce compound (VI bis), which brings us back to the case already examined.

Compounds (A): pyridazones (I) and pyridazinones (VI bis) have a basic character and can be converted into appropriate salts, for example hydrochlorides or organic acid salts to facilitate their utilization.

The examples below are given for the purpose of illustrating the invention.

=morpholino) Stage a.-Synthesis of a-hydroxy-u-methyl-fy-ketofyphenylebutyric -acid (IV).-In a 2-litre conical flask introduce 1 mol. pyruvic acid (III). Neutralize with a 20% potassium hydroxide solution, with stirring and cooling.

After neutralization, add 3 moles of acetophenone (Il) followed by a -solution of 70 g. of KOH in 1000 ml. of methyl alcohol. Under these conditions, the reaction mixture is homogeneous. Leave for 48 hours at room temperature.

At the end of this period of time, neutralize exactly with 10 N H2804 while cooling.

Evaporate the methanol under the vacuum of a filterpump and acidify the remaining solution with 150 ml. of 10 N H2804. Extract with 3 portions of ether, there being employed a total amount of 1250-1500 ml. The ethereal layer is washed with two fractions of water, then extracted with 5 00-7 50 m1. of a 10% KHCO3 solution.

Treat the bicarbonate layer with 150 ml. of l0 N H2804 and the required acid crystallizes after a few moments in an ice bath.

It could occur that the acid does not crystallize at this stage of the preparation. In this case, extract the acidied layer several times with ether. These extracts are washed with a little water, dried on anhydrous MgSO4 and then evaporated under the vacuum of a filter-pump. The acid is then obtained in the form of a crystalline residue.

Filter and wash with a little isopropyl oxide. 77.65 g. of acid in the form of pearl-white crystals are obtained with a yield of 37.5%, it having the empirical formula CHHIZO., (M.W.=208.21, M.P.=131 C).

Centesimal analysis-Theoretical: Carbon, 63.45%; hydrogen, 5.81%. Found: Carbon, 63.87%; hydrogen, 5.87%.

Stage b Preparation of 4-hydroXy-4-methyl-G-phenyl pyridazinone (VI).-In a 250 ml. ask introduce 0.2 mole of a-hydroxy a-methyl 'y-keto ry-phenyl butyric acid (IV) which is dissolved in a little n-butanol. Gradually add `0.22 mole of hydrazine hydrate, then -150 ml. of butanol.

Surmount the flask with a long condenser and distil the binary butanol-water azeotrope at 92 C. About 12 rnl. of water are thus obtained. When the butanol distils in the limpid state, the operation is stopped and the excess of the remaining butanol is eliminated in the ask by evaporation until dry under the vacuum of a filter-pump.

Stage c.-Preparation of 4-methyl 6-phenyl pyridazone (VII).-The yellow crystalline residue obtained after evaporation to dryness in stage b is dissolved in m1. glacial acetic acid and 4 ml. concentrated hydrochloric acid, then left in the oven at 100 C. for 2 hours, while stirring from time to time.

At the end of this time, pour the solution into 420 ml. of Water, while stirring in an ice bath. The pyridazone precipitates with a yield of 90% in the form of white crystals which, when recrystallized from 70% alcohol have the following characteristics: Empirical formula CHHIONZO, M.W.=186.21, M.P.= C.

Centesimal analysis.-Theoretical; Carbon, 70.94%; hydrogen, 5.41%. Found: Carbon, 71.04%; hydrogen, 5.37%.

Stage d.-Synthesis of 2-morpholinoethyl 4-methyl-6- phenyl pyridazone (1).--In a 500 m1. Erlenmeyer ask introduced 0.06 mole of 4-methyl-6-phenyl pyridazone which is dissolved in 45 ml. of absolute alcohol. Add thereto a sodium ethoxide solution prepared :by the action of 0.06 mole of sodium methoxide on 45 m1. of absolute alcohol.

Further, prepare a solution of 0.06 mole of morpholino chlorethane chloride (VIII) in 45 ml. of absolute alcohol to which a sodium ethoxide solution (action of 0.06 mole of CHSONa on 45 rnl. of absolute alcohol) is added. Mix the two solutions and reflux for 8 hours.

Thereafter, filter the sodium chloride formed on a Buchner filter in the vacuum of a filter pump. The filtrate is evaporated to dryness under the vacuum of the filter pump, and the free base is then obtained either in an oily form, which can be purified by a thorough distillation under a vacuum (B.P.=172-180 C. under 0.01 mm. Hg), or in a crystalline form. Before utilizing the crystalline hase, ensure that it is free from any trace of morpholinoethanol lby adding several times absolute alcohol and evaporating each time until dry. The pyridazone (I) thus obtained is then converted into the hydrochloride, as follows:

Dissolve the base obtained in 75 ml. of acetone dried on anhydrous K2CO3 or 40 ml. of isopropanol, and pass through this filtered solution a stream of gaseous HC1. After some time, a fine, white, slightly pink precipitate is formed. Filter on a sintered glass filter and dry.

This precipitate is purified by dissolving it in a minimum amount of 95% alcohol and reprecipitating with ether. It then possesses the following characteristics:

Centesimal analysis-Theoretical: Carbon: 60.79%; hydrogen: 6.60%. Found: Carbon, 60.63%; hydrogen 6.66%. It melts at 89-91 C., its hydrochloride melting at 228-230 C.

When, in stage d, morpholinochlorethane chloride is replaced by dimethylaminochlorethane, diethylaminochlorethane or piperidinochlorethane chloride there is obtained, respectively, 2-dimethylaminoethy1-4-rnethyl-6` phenyl-S-pyridazone (the hydrochloride of which melts at 215 C.), 2-diethylaminoethyl-4-methyl-6-phenyl-3- pyridazone (the hydrochloride of which melts at 198 C.) and 2-piperidinoethyl 4 methyl 6 pheny1-3-pyridazone (the hydrochloride of which melts at 263-264 C.).

EXAMPLE 2 Preparation of 2-morpholinoethy1-4-methyl-6(metamethoxy) phenyl-3 -pyridazone This example illustrates the embodiment involving stages b1 and c1.

The a-hydroxy y-methyl y-keto(metamethoxy)phenyl butyric acid (1V, R=metamethoxy, R1=CH3, R2=H) iS obtained according to the technique described at stage a of Example l.

In a ask surmounted with a rectification column are introduced 28 g. (0.117 mole) of the above named acid dissolved in about 120 ml. of butanol. Thereto are added 17.5 g. (0.117 mole) of morpholinoethylhydrazine (V bis). The water is removed by distillation of the lbutanolwater azeotrope at 92.5 C. Excess butanol is evaporated in vacuo.

The resultant pyridazinone (VI bis) is immediately dissolved in 120 ml. of glacial acetic acid and 24 ml. of concentrated hydrochloric acid. The solution is heated at 100 C. for 2 hours.

To produce the hydrochloride, pour the acetohydrochloric solution in a large excess of water and alcalinize with sodium hydroxide. The pyridazone base precipitates in oily form. It is extracted continuously overnight in ethereal solution.

The ether is evaporated, the corresponding oil is dissolved in anhydrous acetone, and is treated with a stream of gaseous hydrochloric acid.

Operating cautiously, the hydrochloride precipitates on addition of ordinary ether and after scratching.

Recrystallize from absolute alcohol.

Melting point of the hydrochloride: 20S-209 C.

Melting point of the base (regenerated from the hydrochloride): 67-68" C.

EXAMPLE 3 Preparation of 2-morpholinoethyl-4-methyl-6-(metachloro)phenyl3 -pyridazone This example illustrates the embodiment comprising effecting stages b and c in a single step.

The rar-hydroxy a-methyl 'y-keto-y-(metachloro)-phenyl butyric acid (IV, R=metachloro) is obtained according to the technique described at stage a of Example 1.

In a ask surmounted with a fractionation column, introduced 0.1 mole of the above named acid, dissolved in 36 ml. pure glacial acetic acid. To this solution add 0.11 mole of hydrazine hydrate diluted in 36 ml. glacial acetic acid.

Distil slowly 0.7 mole of water, then cool the solution to about -80 C. and add 2.08 m1. of concentrated hydrochloric acid. Distil slowly another 0.1 mole of water. To the still warm solution occupying a volume of 50 ml. add 30 m1. of boiling water. A slight turbidity is formed. Allow to crystallize by letting the solution rest at ambient temperature.

After condensation with morpholinochlorethane, there is obtained 2-morpholinoethyl-4-methyl-6(metachloro) phenyl-S-pyridazone that is transformed into hydrochloride or other salt according to the usual methods.

EXAMPLE 4 Preparation of 2-morpholinoethyl-4-isopropyl-6- phenyl-S-pyridazone (Compound I, R=R2=X=H, Ri=isopropyl, '11:2

/Z1 -N =morpholino) This example illustrates the embodiment according to which stage d is carried out in water.

The 4-isopropyl-6-phenyl-3-pyridazone -is obtained according to stages a, b, c described in Example 1.

Dissolve in the hot 0.05 mole of this pyridazone in ml. of water and 15 ml. of caustic soda lye and add, with stirring, 0.055 mole of morpholinochlorethane chloride dissolved in 20 ml. of water. Stirring of the hot solution is continued for a further fifteen minutes. The pyridazone crystallizes on cooling. After separation of the crystals, the base is transformed into hydrochloride or other salt according to the general methods.

A summary is given in the following tables of the physical chemical properties of the compounds obtained according to the above examples together with those of other compounds according to the invention obtained in analogous fashion. The tables give also the LD50 in mg./ kg. of these compounds, determined in mice by intraperitoneal route, unless otherwise indicated.

Empirical Code R R1 (GHX) Zz formula Melting Point, C. No. LD5

H CH3 CHT-CH2 Morpholino- CnHzlNgOz Hydroehlorde, 228-230; sulfamate, 164-184 246 l 475 (dec); aspartate, 91-92 and 269.

H CH3 CHQ- CHz--CHz .---.dO ClsHztNsOz Hydl'OChlOIde, 252 263 245 H CH3 (JH-CH2 do CisHzsNsOz Hydrochloride, 162 364 185 CH2 .do CmHnNgOz Hydroehloride, 153-154, base, 114 (dec.) 250 800 CH2-CH2 Plperldino- CigHmNaO Hydrochloride, 263-264 245 i CH2-CH2 Pyrrolrdino- CnHziNaO Hydrochloride, 246. 354 2 on, Morini- CHHITNSO Hydrochlonde, 125... 251

CH2-C H2 N (CH3) 2. C15H19Na0 HydIOChlOl'de, 215 247 CH2-CH2 N(C2H5)2 CnHuNzO Hydrochloride, 198 244 2 140 CHZ-CHZ-CHz N (CH3) 2. CzeHziNaO Hydl'OChlOl'de, 201-203 368 /CHs H CH3 CH2-CH2 N CH) 2 CisHz'lNaO HydrOGhlOl'de, 222 367 155 See footnotes rut end of table.

TABLE I-Contnued /71 N Empirical Code R R1 (CHX) n- Zg formula Melting Point, C. No. LD50 CH3 CH2-CH2 Morpholno--- C17H21N3O3 Hydrochloride, 245 (dec): paSty at 192-4, 252 930 base 1GO-168, pasty at 105. CH3 CHT-CH2 .do CliHzaNiOa Hydrochloride, 235-240; base, 92. 254 450 CH3 CHT-CH2 d C1sH23N302 HydlOChlOl'de, 210; base, 83,". 255 415 CH3 CH2- a CiiHzoNaOzCl Hydrochloride, 225; base, 106." 259 220 CH3 CH2-CE1 O2 Hydrocliloride, 175; base, 824 264 458 CH3 CH2-CH2 CnHzsNaOs Hydrochloride, 208-209; base, 67-68. 270 440 CH; CHz-CHz -do CivHzoNsOzCl Hydrochloride, 230; base, 131. 268 300 CH; CH2-CH2 O3 Hydrochloride, 232 272 430 CH3 CH2-CH2 02 HydrOChlOride, 230-233 258 295 CH3 CH2-CH2 do CiiHzoNaOzCl Hydrochloride, 204205 267 320 CH3 CH2-CH2 dO C1gH23N3O2 HydIOChlOde, 213-215 269 345 CH3 CH2-CH2 N (CH3)2 CMH, 3 2 Hydrochloride, 209w214; base, 14C-3.- 256 330 CH3 CH2-CH2 N (CHM CisHiiNaO Cl Hydrochloride, 194; base, 74 260 210 CH2-CH3 CHT-CH2 Morpholino- ClgHggNaOz Hydrochloride, 1S0-182. 329 240 CH2-CH3 CH2-CH2 N (C2H5)z- C1sHz5N3O Hydrohloride, 152 357 138 CH2-CH3 CH2-CH2 N(CH3)2 CiHziNaO HydrOGhlOl'de, 142 365 118 CHT-CH3 CH2-CH2 Pyrrolidiiio-.. CigHzgNgO Hydrochloride, 215 356 120 GHz-CH3 CH-CHa Morpholino--- C1gH25N 302 Hydrochloride, 150-151 363 128 CH3 GHz-GHz-CH; CH2-CH2 ..-..do C10H25N302 Hydrochloride, 178 352 220 CH(CH3)2 CHT-CH2 Hydrochlorde, 202..- 350 275 H (0111030111 CH2-CH2 dO CgHnNOg HydrOGhlOride, 165 349 162 l Per os 1,300. 2 Per os 690.

TABLE II.PYRIDAZONES (D-RF-CHX- Empirical Code R R1 -(ClIX)- Z2 formula Melting Point, G. N o. LD00 H CH3 CH2-CH2 Morpholino-.- CigHaaNOz Hydrocliloride, 245 257 370 TABLE IIL-PYRIDAZINONES (VI biS)-R2=H Empirical Code R Ri (CHX) Zz formula Melting Point, C. N o. LD50 H CHS CH2-CH2 Morpholino--- CnHnNaOa Hydrochlorlde, 226 262 550 p-OH CH; CH2-CH2 do Ci1H2aN3O4 Hydrochloride, 240; base, 175---. 253 930 As indicated previously, compounds (A) have a psychothe tail is carried out every thirty minutes during 2.5

tropic activity that was made apparent by means of the hours. three pharmacological tests described below: Were considered as particularly active those compounds 1) The tirst of these tests measures the inhibition of that extended by 3-4 seconds the reaction time of the the number of twisting movements produced in mice on animal at a dosage equivalent to one-fifth of the LD50. intraperitoneal injection of 0.25 ml. per mouse of a para- These particularly active compounds were the followquinone solution containing 25 mg. per 100 rnl. 50 ing (listed under their code numbers):

The test compounds are administered to the animals ten 246 260 minutes before the paraquinone injection and the twist- 264 363 ing movements are counted during one hour for each 270 350 animal. 268 349 Generally, injection of paraqunone alone causes fifty 262 twisting movements per hour; were considered as being particularly active those compounds that inhibited more than 70% of such twisting movements at a dosage equivalent to one-fifth of the LD50.

These particularly active compounds were the following (listed under their code number):

(3) The third test used was the study of the behaviour of mice and rats under the influence of a dosage equivalent to one-lifth of the LD50 of the test compounds. This behaviour being evaluated with respect to the systemic sedation with decu-bitus or, on the contrary, by observing the aggressivity or the increased motivity of the ani- 246 260 mals 364 365 l 259 356 Were found particularly sedative, according to this test, 270 350 the products listed under the code numbers: 268 349 246 352 262 g 350 (2) The second of these tests measures the reaction 269 time of mice to immersion of the tail of the animal in 70 329 water heated to a temperature of 58 C.

When no product has been administered to the animal, the animal moves its tail after 11/2 seconds. 263 367 The test compounds are administered to the animal 354 256 fifteen minutes before the first immersion; immersion of 368 260 Were found particularly stimulating:

Having now described my invention, what I claim as new and desire to secure by Letters Patent is;

1. Acompound of formula R2 Ri wherein R is a substituent in any one of lthe ortho, metaand para-positions selected from the group consisting of hydrogen, halogens and lower alkyl, lower alkoxy and hydroxy groups,

R1 is an alkyl group having 1-4 carbon atoms,

R2 is a member selected from the group consisting of hydrogen and alkyl groups having 1-4 carbon atoms,

X is a member selected from the group consisting of hydrogen and lower alkyl groups,

n is an integer from l to 3, Ithe various Xs, when n is greater than 1, not being necessarily ident-ical,

Z1 :and Z2 are each a member selected from the group consisting of lower alkyl groups, and radicals such as Z1 and Z2 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of morpholino, piperidino and pyrrolidino,

R3 is a member selected from the group consisting of hydrogen and a free valency forming a double bond with R1and R4 is a member selected from the group consisting of the hydroxyl group vand la free valency forming ya double bond with R3, and its non-toxic acid addition salts.

pyridazone and the non-toxic lacid addition salts thereof.

phenyl3-pyridazone and the non-toXic acid addition salts thereof.

pyridazonc and the non-toxic acid addition salts thereof.

5 pyridazinone and the non-toxic acid addition salts thereof.

7. A compound of formula:

N-NH

wherein: R is a substitutent in any one of the ortho, -metaand para-positions, selected from the group consisting of hydrogen, halogens, and lower alkyl, lower alkoxy and hydroxy groups, R1 is an alkyl group hav-ing I14 carbon atoms, and R2 is la member selected from the group consisting of hydrogen and the alkyl groups having 1-4 carbon Mustafa et al.: Tetrahedron, vol. (March 1964),

HENRY R. JILES, Primary Examiner.

I. M. FORD, Assistant Examiner.

U.s. c1. X.R. 

